Development of a vaccine able to prevent HIV infection would play a major role in managing the spread of HIV. A recently developed class of vaccines that use DNA as the immunizing agent offers a promising approach because genetic vaccination in animal models results in a broader immune response, including the induction of cytotoxic T-cell responses, than protein vaccines can achieve. Apollon, Inc. (now part of Wyeth Ayerst Vaccines) has developed a genetic vaccine encoding the envelope protein of HIV-1 that has been shown to be immunogenic in animal studies and has undergone early evaluation as an immunomodulating agent in HIV-infected patients. In collaboration with Apollon, Inc., we have undertaken a study in up to 41 individuals not infected with HIV. The study will involve administration of four doses of the genetic vaccine or a similarly constituted vehicle control over a 6-month period, with a followup of 6 additional months. Four dose levels of the vaccine will be used. To date, 27 volunteers have enrolled in the study and immunizations have been well tolerated. The study will focus on evaluating the safety and immunogenicity of this candidate vaccine, including its ability to induce cytotoxic T-cell responses.